Development of a Suicide Inhibition-Based Protein Labeling Strategy for Nicotinamide N-Methyltransferase
| Autor: | Sudeshna Sen, Eranthie Weerapana, Li Zheng, Walter Fast, Ari J. Salinger, Paul R. Thompson, Santanu Mondal |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Nicotinamide N-methyltransferase 01 natural sciences Biochemistry Methylation Catalysis Article 03 medical and health sciences chemistry.chemical_compound Biosynthesis Nicotinamide N-Methyltransferase Humans chemistry.chemical_classification Nicotinamide 010405 organic chemistry Proteins General Medicine 0104 chemical sciences Kinetics 030104 developmental biology Enzyme HEK293 Cells chemistry Suicide inhibition Molecular Medicine NAD+ kinase Cysteine |
| Zdroj: | ACS chemical biology. 14(4) |
| ISSN: | 1554-8937 |
| Popis: | Nicotinamide N-methytransferase (NNMT) catalyzes the S-adenosyl-L-methionine (SAM)-dependent methylation of nicotinamide (NAM) to form N-methylnicotinamide (Me-NAM). This enzyme detoxifies xenobiotics and regulates NAD(+) biosynthesis. Additionally, NNMT is overexpressed in various cancers. Herein, we describe the first NNMT-targeted suicide substrates. These compounds, which include 4-chloropyridine and 4-chloronicotinamide, exploit the broad substrate scope of NNMT; methylation of the pyridine nitrogen enhances the electrophilicity of the C4 position, thereby promoting an aromatic nucleophilic substitution by C159, a non-catalytic cysteine. Based on this activity, we developed a suicide inhibition-based protein labeling (SIBLing) strategy using an alkyne-substituted 4-chloropyridine that selectively labels NNMT in vitro and in cells. In total, this study describes the first NNMT-directed activity-based probes. |
| Databáze: | OpenAIRE |
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